ABSTRACT
The design of boron-based molecular rotors stems from boron-carbon binary clusters containing multiple planar hypercoordinate carbons (phCs, such as C2B8). However, the design of boron-coordinated phCs is challenging due to boron's tendency to occupy hypercoordinate centers more than carbon. Although this challenge has been addressed, the designed clusters of interest have not exhibited dynamic fluxionality similar to that of the initial C2B8. To address this issue, we report a σ/π doubly aromatic CB2H5+ cluster, the first global minimum containing a boron-coordinated planar tetracoordinate carbon atom with dynamic fluxionality. Dynamics simulations show that two ligand H atoms exhibit alternate rotation, resulting in an intriguing dynamic fluxionality in this cluster. Electronic structure analysis reveals the flexible bonding positions of the ligand H atoms because they do not participate in π delocalized bonding nor bond to any other non-carbon atom, highlighting this rotational fluxionality. Unprecedentedly, the fluxional process involves not only the usual conversion of the number of bonding atoms, but also the type of bonding (3c π bonds â 4c σ bonds), which is an uncommon fluxional mechanism. The cluster represents an effort to apply phC species to molecular machines.
ABSTRACT
SARS-CoV-2 has caused global waves of infection since December 2019 and continues to persist today. The emergence of SARS-CoV-2 variants with strong immune evasion capabilities has compromised the effectiveness of existing vaccines against breakthrough infections. Therefore, it is important to determine the best utilization strategies for different demographic groups given the variety of vaccine options available. In this review, we will discuss the protective efficacy of vaccines during different stages of the epidemic and emphasize the importance of timely updates to target prevalent variants, which can significantly improve immune protection. While it is recognized that vaccine effectiveness may be lower in certain populations such as the elderly, individuals with chronic comorbidities (e.g., diabetes with poor blood glucose control, those on maintenance dialysis), or those who are immunocompromised compared to the general population, administering multiple doses can result in a strong protective immune response that outweighs potential risks. However, caution should be exercised when considering vaccines that might trigger an intense immune response in populations prone to inflammatory flare or other complications. In conclusion, individuals with special conditions require enhanced and more effective immunization strategies to prevent infection or reinfection, as well as to avoid the potential development of long COVID.
ABSTRACT
Protection suits are vital for firefighters' safety. Traditional protection suits physically protect firemen from burns, but cannot locate the position of bodily injuries caused by impact debris. Herein, we present a wearable impact debris positioning system for firefighter protection suits based on an accelerometer array. Wearable piezoelectric accelerometers are distributed regularly on the suit to detect the vibration on different body parts, which is conducive to determining the position of injured body parts. In addition, the injured parts can be displayed on a dummy body model on the upper computer with a higher localization accuracy of 4 cm. The positioning alarm system has a rapid response time of 0.11 ms, attributed to the smart signal processing method. This work provides a reliable and smart method for locating and assessing the position of bodily injuries caused by impact debris, which is significant because it enables fire commanders to rescue injured firefighters in time.
Subject(s)
Accelerometry , Firefighters , Accelerometry/instrumentation , Humans , Protective Clothing , Wearable Electronic Devices , VibrationABSTRACT
SARS-CoV-2 infection starts from the association of its spike 1 (S1) subunit with sensitive cells. Vesicular endothelial cells and platelets are among the cell types that bind SARS-CoV-2, but the effectors that mediate viral attachment on the cell membrane have not been fully elucidated. Herein, we show that P-selectin (SELP), a biomarker for endothelial dysfunction and platelet activation, can facilitate the attachment of SARS-CoV-2 S1. Since we observe colocalization of SELP with S1 in the lung tissues of COVID-19 patients, we perform molecular biology experiments on human umbilical vein endothelial cells (HUVECs) to confirm the intermolecular interaction between SELP and S1. SELP overexpression increases S1 recruitment to HUVECs and enhances SARS-CoV-2 spike pseudovirion infection. The opposite results are determined after SELP downregulation. As S1 causes endothelial inflammatory responses in a dose-dependent manner, by activating the interleukin (IL)-17 signaling pathway, SELP-induced S1 recruitment may contribute to the development of a "cytokine storm" after viral infection. Furthermore, SELP also promotes the attachment of S1 to the platelet membrane. Employment of PSI-697, a small inhibitor of SELP, markedly decreases S1 adhesion to both HUVECs and platelets. In addition to the role of membrane SELP in facilitating S1 attachment, we also discover that soluble SELP is a prognostic factor for severe COVID-19 through a meta-analysis. In this study, we identify SELP as an adhesive site for the SARS-CoV-2 S1, thus providing a potential drug target for COVID-19 treatment.
Subject(s)
Blood Platelets , COVID-19 , Human Umbilical Vein Endothelial Cells , P-Selectin , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , P-Selectin/metabolism , SARS-CoV-2/physiology , COVID-19/virology , Blood Platelets/metabolism , Virus Attachment/drug effectsABSTRACT
BACKGROUND: Growing evidence suggests that symptoms associated with post-COVID-19 condition (also known as long COVID) can affect multiple organs and systems in the human body, but their association with viral persistence is not clear. The aim of this study was to investigate the persistence of SARS-CoV-2 in diverse tissues at three timepoints following recovery from mild COVID-19, as well as its association with long COVID symptoms. METHODS: This single-centre, cross-sectional cohort study was done at China-Japan Friendship Hospital in Beijing, China, following the omicron wave of COVID-19 in December, 2022. Individuals with mild COVID-19 confirmed by PCR or a lateral flow test scheduled to undergo gastroscopy, surgery, or chemotherapy, or scheduled for treatment in hospital for other reasons, at 1 month, 2 months, or 4 months after infection were enrolled in this study. Residual surgical samples, gastroscopy samples, and blood samples were collected approximately 1 month (18-33 days), 2 months (55-84 days), or 4 months (115-134 days) after infection. SARS-CoV-2 was detected by digital droplet PCR and further confirmed through RNA in-situ hybridisation, immunofluorescence, and immunohistochemistry. Telephone follow-up was done at 4 months post-infection to assess the association between the persistence of SARS-CoV-2 RNA and long COVID symptoms. FINDINGS: Between Jan 3 and April 28, 2023, 317 tissue samples were collected from 225 patients, including 201 residual surgical specimens, 59 gastroscopy samples, and 57 blood component samples. Viral RNA was detected in 16 (30%) of 53 solid tissue samples collected at 1 month, 38 (27%) of 141 collected at 2 months, and seven (11%) of 66 collected at 4 months. Viral RNA was distributed across ten different types of solid tissues, including liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. Additionally, subgenomic RNA was detected in 26 (43%) of 61 solid tissue samples tested for subgenomic RNA that also tested positive for viral RNA. At 2 months after infection, viral RNA was detected in the plasma of three (33%), granulocytes of one (11%), and peripheral blood mononuclear cells of two (22%) of nine patients who were immunocompromised, but in none of these blood compartments in ten patients who were immunocompetent. Among 213 patients who completed the telephone questionnaire, 72 (34%) reported at least one long COVID symptom, with fatigue (21%, 44 of 213) being the most frequent symptom. Detection of viral RNA in recovered patients was significantly associated with the development of long COVID symptoms (odds ratio 5·17, 95% CI 2·64-10·13, p<0·0001). Patients with higher virus copy numbers had a higher likelihood of developing long COVID symptoms. INTERPRETATION: Our findings suggest that residual SARS-CoV-2 can persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and long COVID symptoms. Further research is needed to verify a mechanistic link and identify potential targets to improve long COVID symptoms. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and New Cornerstone Science Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/epidemiology , COVID-19/diagnosis , COVID-19/virology , Cross-Sectional Studies , SARS-CoV-2/isolation & purification , Male , Female , Middle Aged , China/epidemiology , Adult , Cohort Studies , Aged , Lung/virologyABSTRACT
Realization of planar tetracoordinate arrangements of nitrogen atoms is challenging because their preference for localized bonding (caused by its high electronegativity) makes them typically tricoordinate. This is especially true for the more electronegative oxygen atoms. Herein, we computationally designed two clusters NBe4H4- and OBe4H4; they contain a planar tetracoordinate nitrogen (ptN) and planar tetracoordinate oxygen (ptO) atom, respectively. Remarkably, the former is a dynamically stable global minimum, while the latter is not. The bonding analysis proves that planar tetracoordination in NBe4H4- favors over tricoordination because of the presence of multicenter delocalized bonds. In contrast, the planar tricoordination dominates due to its weak delocalized bonding ability of oxygen in the OBe4H4 cluster. Moreover, the 6σ/2π double aromaticity due to multicenter delocalized bonds allows the NBe4H4- cluster to obtain additional stability. This cluster is a promising synthetic due its dynamic and thermodynamic stability.
ABSTRACT
Acute lung injury (ALI) is an important pathological process of acute respiratory distress syndrome, yet there are limited therapies for its treatment. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to be effective in suppressing inflammation. However, the effects of MSCs-Exo on ALI and the underlying mechanisms have not been well elucidated. Our data showed that MSCs-Exo, but not exosomes derived from MRC-5 cells (MRC-5-Exo), which are human fetal lung fibroblast cells, significantly improved chest imaging, histological observations, alveolocapillary membrane permeability, and reduced inflammatory response in ALI mice model. According to miRNA sequencing and proteomic analysis of MSCs-Exo and MRC-5-Exo, MSCs-Exo may inhibit pyroptosis by miRNAs targeting caspase-1-mediated pathway, and by proteins with immunoregulation functions. Taken together, our study demonstrated that MSCs-Exo were effective in treating ALI by inhibiting the pyroptosis of alveolar macrophages and reducing inflammation response. Its mechanism may be through pyroptosis-targeting miRNAs and immunoregulating proteins delivered by MSCs-Exo. Therefore, MSCs-Exo may be a new treatment option in the early stage of ALI.
Subject(s)
Acute Lung Injury , Exosomes , Mesenchymal Stem Cells , MicroRNAs , Mice , Animals , Humans , Macrophages, Alveolar/metabolism , Pyroptosis , Exosomes/metabolism , Proteomics , Acute Lung Injury/therapy , MicroRNAs/genetics , MicroRNAs/metabolism , Inflammation/metabolism , Mesenchymal Stem Cells/metabolismABSTRACT
Hypertensive intracerebral hemorrhage (ICH) is a devastating condition, the molecular underpinnings of which remain not fully understood. By leveraging high-throughput transcriptome sequencing and network pharmacology analysis, this study unveils the significant role of the tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) in ICH pathogenesis. Compared to controls, a conspicuous downregulation of TIE2 was observed in the cerebral blood vessels of hypertensive ICH mice. In vitro assays with human brain microvascular endothelial cells (HBMEC), HBEC-5i revealed that modulation of TIE2 expression significantly influences cellular proliferation, migration, and angiogenesis, mediated via the Rap1/MEK/ERK signaling pathway. Notably, the small molecule AKB-9778 was identified to target and activate TIE2, affecting the functional attributes of HBEC-5i. In vivo experiments further demonstrated that combining AKB-9778 with antihypertensive drugs could mitigate the incidence and volume of bleeding in hypertensive ICH mouse models, suggesting potential therapeutic implications.
Subject(s)
Aniline Compounds , Endothelial Cells , Intracranial Hemorrhage, Hypertensive , Sulfonic Acids , Animals , Humans , Mice , Brain/metabolism , Cerebral Hemorrhage/metabolism , Endothelial Cells/metabolism , Intracranial Hemorrhage, Hypertensive/metabolism , Receptor, TIE-2/genetics , Receptor, TIE-2/metabolismABSTRACT
Acute carbon monoxide poisoning (ACOP) causes tissue hypoxia and damage mainly by binding to hemoglobin (Hb). This article aimed to explore the changes in the activity of nuclear factor kappa-B (NF-κB) pathway in the hippocampus after ACOP and its role in nerve cell damage. This article used 30 Sprague-Dawley (SD) rats as the research object, which were randomly divided into two groups, ACOP group and controls. The model of carbon monoxide (CO) poisoning was established, and then the activity of NF-κB pathway in the hippocampus of the two groups of rats was detected, and the statistical analysis was performed. Compared with the controls, the activity of NF-κB pathway in the hippocampus of the ACOP group was significantly increased (P < 0.05). The degree of neuronal damage in the ACOP group was also significantly increased. ACOP increases the activity of the NF-κB pathway in the hippocampus and may cause neuronal damage through this pathway. This provides new ideas and methods for the treatment of ACOP, and also provides new evidence for the role of NF-κB pathway in neuronal injury.
Subject(s)
Carbon Monoxide Poisoning , Hippocampus , NF-kappa B , Neurons , Rats, Sprague-Dawley , Signal Transduction , Carbon Monoxide Poisoning/metabolism , Carbon Monoxide Poisoning/pathology , Animals , Hippocampus/metabolism , Hippocampus/pathology , NF-kappa B/metabolism , Male , Neurons/metabolism , Neurons/pathology , Rats , Acute DiseaseABSTRACT
BACKGROUND: SARS-CoV-2-specific adaptive immunity more than 1 year after initial infection has not been well characterised. The aim of this study was to investigate the durability and cross-reactivity of immunological memory acquired from natural infection against SARS-CoV-2 in individuals recovered from COVID-19 2 years after infection. METHODS: In this longitudinal cohort study, we recruited patients who had recovered from laboratory-confirmed COVID-19 and were discharged from Jinyintan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. We carried out three successive follow-ups between June 16 and Sept 3, 2020 (6 months), Dec 16, 2020, and Feb 7, 2021 (1 year), and Nov 16, 2021, and Jan 10, 2022 (2 years), in which blood samples were taken. We included participants who did not have re-infection or receive a SARS-CoV-2 vaccination (infected-unvaccinated), and participants who received one to three doses of inactivated vaccine 1-2 years after infection (infected-vaccinated). We evaluated the presence of IgG antibodies, neutralising antibodies, and memory B-cell and memory T-cell responses against the prototype strain and delta and omicron variants. FINDINGS: In infected-unvaccinated participants, neutralising antibody titres continually declined from 6-month to 2-year follow-up visits, with a half-life of about 141·2 days. Neutralising antibody responses to omicron sublineages (BA.1, BA.1.1, BA.2, BA.4/5, BF.7, BQ.1, and XBB) were poor. Memory B-cell responses to the prototype strain were retained at 2 years and presented cross-reactivity to the delta and omicron BA.1 variants. The magnitude of interferon γ and T-cell responses to SARS-CoV-2 were not significantly different between 1 year and 2 years after infection. Multifunctional T-cell responses against SARS-CoV-2 spike protein and nucleoprotein were detected in most participants. Recognition of the BA.1 variant by memory T cells was not affected in most individuals. The antibody titres and the frequencies of memory B cells, but not memory T cells, increased in infected-vaccinated participants after they received the inactivated vaccine. INTERPRETATION: This study improves the understanding of the duration of SARS-CoV-2-specific immunity without boosting, which has implications for the design of vaccination regimens and programmes. Our data suggest that memory T-cell responses primed by initial viral infection remain highly cross-reactive after 2 years. With the increasing emergence of variants, effective vaccines should be introduced to boost neutralising antibody and overall T-cell responses to newly emerged SARS-CoV-2 variants. FUNDING: Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities for Peking Union Medical College, Beijing Natural Science Foundation, UK Medical Research Council.
Subject(s)
COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Longitudinal Studies , Immunologic Memory , COVID-19/epidemiology , COVID-19 Vaccines , Cohort Studies , Antibodies, Neutralizing , Vaccines, InactivatedABSTRACT
RATIONALE: Patients who have myasthenia gravis or dermatomyositis show clinical signs of muscular weakening. Ocular muscle involvement is uncommon, and symmetrical proximal limb weakness is the typical presentation of dermatomyositis. However, the earliest and most noticeable sign in those with myasthenia gravis is extraocular muscular paralysis. Dermatomyositis is frequently complicated by malignancy, and the common malignancies associated with dermatomyositis vary by region and ethnicity, while thymoma is relatively rare. About 10% to 15% of people with myasthenia gravis have thymoma, which is involved in the etiology of the disease. PATIENT CONCERNS: A 68-year-old female presented with ocular muscle weakness for 10 days that manifested as bilateral blepharoptosis with the phenomenon of "light in the morning and heavy in the evening." Imaging examination showed anterior mediastinal thymic tumor with metastasis. DIAGNOSES: After a thorough physical examination, we discovered bilateral upper limbs with grade IV muscle strength and the typical rash of dermatomyositis. In combination with elevated serum kinase levels and electromyography suggesting myogenic damage, the patient was finally diagnosed as dermatomyositis with multiple metastases of thymoma. INTERVENTIONS: The patient received oral hydroxychloroquine sulfate, topical corticosteroids, and tacrolimus ointment, but these did not work very well. Subsequently, the patient underwent surgery combined with radiotherapy for the thymoma. OUTCOMES: Muscle weakness in the patient improved after effective treatment of tumor, and the rash mostly disappeared. CONCLUSION: Ocular muscle weakness and thymoma are more common in myasthenia gravis, but we cannot ignore the possibility of dermatomyositis. To further establish the diagnosis, a thorough physical examination and laboratory findings are required. Further tumor screening should be performed for patients with dermatomyositis. Early detection and management of possible tumors are essential to the treatment of dermatomyositis linked to malignancies.
Subject(s)
Dermatomyositis , Exanthema , Myasthenia Gravis , Thymoma , Thymus Neoplasms , Female , Humans , Aged , Thymoma/complications , Thymoma/diagnosis , Thymoma/surgery , Dermatomyositis/diagnosis , Dermatomyositis/complications , Myasthenia Gravis/drug therapy , Thymus Neoplasms/complications , Thymus Neoplasms/diagnosis , Thymus Neoplasms/surgery , Muscle Weakness , Exanthema/complicationsABSTRACT
BACKGROUND: As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified. METHODS: Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID. FINDINGS: The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder. INTERPRETATION: The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID. FUNDING: National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program.
Subject(s)
COVID-19 , Cardiomyopathy, Dilated , Humans , Male , Female , Cohort Studies , Longitudinal Studies , Post-Acute COVID-19 Syndrome , Proteomics , Biomarkers , Survivors , CholesterolABSTRACT
Background: Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far. Methods: The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors. Results: We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis. Conclusion: We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.
ABSTRACT
Accumulating articles have reported the coding potential of long non-coding RNAs (lncRNAs). However, only a few lncRNAs-encoded peptides have been studied. Breast cancer (BRCA) progression-related gene modules were determined by weighted gene co-expression network analysis (WGCNA). Cell viability, proliferation, and migration capacities were assessed by Cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays. Immunofluorescence (IF) assay was implemented to observe protein expression. Co-immunoprecipitation (Co-IP) and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) were employed to analyze MAGI2 antisense RNA 3 (MAGI2-AS3)-ORF5-interacted proteins. WGCNA identified that MEpurple and MEblack modules were significantly negatively correlated with T stage in BRCA patients. MAGI2-AS3 was screened as one of the differentially expressed (DE) lncRNAs with translational potential in MEblack and MEpurple modules in BRCA. The data in The Cancer Genome Atlas (TCGA) uncovered that MAGI2-AS3 abundance was significantly decreased in invasive BRCA patients, and it had high diagnostic and prognostic values. MAGI2-AS3-ORF5 notably restrained BRCA cell viability, proliferation, and migration. Mechanically, MAGI2-AS3-ORF5 might affect the progression of BRCA cells by binding to extracellular matrix (ECM)-related proteins. MAGI2-AS3-ORF5 played an anti-tumor role by inhibiting BRCA cell viability, proliferation, and migration. MAGI2-AS3-ORF5 might modulate BRCA cell migration through ECM-associated proteins.
ABSTRACT
(-)-Epigallocatechin-3-gallate (EGCG) is the primary active ingredient in green tea and has been used for cancer prevention in clinical trials. The anti-tumor effects of EGCG stem from its ability to inhibit the activities of many oncoproteins, such as AKT, VEGFR, STAT3, and mutant p53. However, the clinical efficacy of EGCG is unsatisfactory. How to improve the anti-tumor effects of EGCG is an open question. Here we report that EGCG inhibits the tumor suppressive Hippo signaling pathway and activates downstream YAP in colorectal cancer (CRC) cells. Activation of YAP impedes the anti-tumor effects of EGCG. YAP blockade increases the sensitivity of CRC cells to EGCG treatment.
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BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, demonstrating rapid progression of pulmonary hypertension (PH) and respiratory failure. Although a number of treatments have been attempted for patients diagnosed with or suspected of having PTTM, successful-treated cases of PTTM were mainly from imatinib therapy, which was a PDGF receptor inhibitor. Anlotinib was a novel tyrosine kinase inhibitor that targets VEGFR, FGFR, PDGFR, and c-kit. CASE PRESENTATION: We reported a patient of PTTM associated with gastric carcinoma, whom were treated with anlotinib, thereby exhibiting significant improvement of PH and respiratory dysfunction. CONCLUSION: Our case provides a new understanding of therapy to PTTM, with implications for defining anlotinib as candidate drug for PTTM. Clinical diagnosis and prompt initiation of anlotinib might be one of the strategies in patients with unstable PTTM.
ABSTRACT
Pulmonary fibrosis is characteristic of several human lung diseases that arise from various causes. Given that treatment options are fairly limited, mouse models continue to be an important tool for developing new anti-fibrotic strategies. In this study, intrapulmonary administration of bleomycin (BLM) is carried out by nasal nebulization to create a mouse model of pulmonary fibrosis that closely mimics clinical disease characteristics. C57BL/6 mice received BLM (7 U/mL, 30 min/day) by nasal nebulization for 3 consecutive days and were sacrificed on day 9, 16, or 23 to observe inflammatory and fibrotic changes in lung tissue. Nasal aerosolized BLM directly targeted the lungs, resulting in widespread and uniform lung inflammation and fibrosis. Thus, we successfully generated an experimental mouse model of typical human pulmonary fibrosis. This method could easily be used to study the effects of the administration of various nasal aerosols on lung pathophysiology and validate new anti-inflammatory and anti-fibrotic treatments.
Subject(s)
Pneumonia , Pulmonary Fibrosis , Humans , Animals , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Bleomycin/pharmacology , Mice, Inbred C57BL , Lung/pathology , Disease Models, AnimalABSTRACT
This study focused on an ozone pollution event occurring in winter (January) in Guangzhou. Various influencing factors were analyzed, including various atmospheric trace gases, meteorological conditions during the whole pollution process, as well as the characteristics of the main O3 precursor volatile organic compounds (VOCs). The main sources of VOCs and the O3 formation regime were analyzed using an array of tools:the ozone potential formation (OFP), positive matrix factorization (PMF) model, and empirical kinetic modeling approach (EKMA) curve. Feasible strategies for O3 control were suggested. The results showed that O3 and NO2 exceeded the corresponding standards in this winter pollution event, when the concentrations of PM10 and PM2.5 were also high, differing from the air pollution characteristics in summer and autumn. Low boundary layer height (<75 m) and high atmospheric stability at night exacerbated the accumulation of ozone precursors and fine particles. Meteorological conditions such as the increased daytime temperature (5â), stronger solar radiation (10%), and low horizontal wind speed (<1 m·s-1) favored photochemical reactions and promoted the formation of ozone and fine particles. VOCs were mainly composed of alkanes, and the proportions of alkanes and alkynes in winter were higher than those in the other seasons. Aromatics (xylenes and toluene) and propylene were the key VOCs species leading to O3 formation. The main VOCs sources were vehicle exhaust (22.4%), solvent usage (20.5%), and industrial emissions (17.9%); however, the source with highest OFP was identified as solvent usage. O3 formation in this event was in the VOCs-limited regime, and reducing O3 precursors in the VOCs/NOx ratio of 3:1 was effective and feasible for O3 control. This study explored the causes of an O3 pollution event in winter, which will serve as reference for the synergistic control of O3 and PM2.5 in heavy pollution seasons.
Subject(s)
Air Pollutants , Ozone , Volatile Organic Compounds , Air Pollutants/analysis , Alkanes/analysis , Alkynes/analysis , China , Environmental Monitoring , Nitrogen Dioxide/analysis , Ozone/analysis , Particulate Matter/analysis , Seasons , Solvents/analysis , Toluene/analysis , Volatile Organic Compounds/analysis , XylenesABSTRACT
Anticancer peptides are promising drug candidates for cancer treatment, but the short circulation time and low delivery efficiency limit their clinical applications. Herein, we designed several lasso-like self-assembling anticancer peptides (LASAPs) integrated with multiple functions by a computer-aided approach. Among these LASAPs, LASAP1 (CRGDKGPDCGKAFRRFLGALFKALSHLL, 1-9 disulfide bond) was determined to be superior to the others because it can self-assemble into homogeneous nanoparticles and exhibits improved stability in serum. Thus, LASAP1 was chosen for proving the design idea. LASAP1 can self-assemble into nanoparticles displaying iRGD on the surface because of its amphiphilic structure and accumulate to the tumor site after injection because of the EPR effect and iRGD targeting to αVß3 integrin. The nanoparticles could disassemble in the acidic microenvironment of the solid tumor, and cleaved by the overexpressed hK2, which was secreted by prostate tumor cells, to release the effector peptide PTP-7b (FLGALFKALSHLL), which was further activated by the acidic pH. Therefore, LASAP1 could target the orthotopic prostate tumor in the model mice after intraperitoneal injection and specifically inhibit tumor growth, with low systematic toxicity. Combining the multiple targeting functions, LASAP1 represents a promising design of self-delivery of peptide drugs for targeted cancer treatments.
Subject(s)
Antineoplastic Agents , Nanoparticles , Prostatic Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Computer-Aided Design , Disulfides , Drug Delivery Systems , Humans , Integrins , Male , Mice , Nanoparticles/chemistry , Peptides/chemistry , Prostatic Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
Global minima (CBe4- and NBe4-) with planar tetracoordinate carbon and nitrogen atoms are stabilized by multicentric bonds. Their unusual anti-aromaticity is due to the strong localized Be-Be bonds preventing the full delocalization of the electrons in the CBe4/NBe4 skeleton. These binary mono-anions are expected to be experimentally realized in the gas phase.